Outcomes With First-Line PD-1/PD-L1 Inhibitor Monotherapy for Metastatic Renal Cell Carcinoma (mRCC): A Multi-Institutional Cohort

Abstract

Introduction: The treatment landscape of metastatic renal cell carcinoma has advanced significantly with the approval of combination regimens containing an immune checkpoint inhibitor (ICI) for patients with treatment-naïve disease. Little information is available regarding the activity of single-agent ICIs for patients with previously untreated mRCC not enrolled in clinical trials. Methods: This retrospective, multicenter cohort included consecutive treatment-naïve mRCC patients from six institutions in the United States who received ≥1 dose of an ICI outside a clinical trial, between June 2017 and October 2019. Descriptive statistics were used to analyze outcomes including objective best response rate (ORR), progression-free survival (PFS), and tolerability. Results: The final analysis included 27 patients, 70% men, median age 64 years (range 42-92), 67% Caucasian, and 33% with ECOG 2 or 3 at baseline. Most patients had intermediate risk (85%, IMDC) with clear cell (56%), papillary (26%), unclassified (11%), chromophobe (4%), and translocation (4%) RCC. All patients had evidence of metastatic disease involving the lungs (59%), lymph node (41%), CNS (19%), liver (11%), adrenal gland (11%), and bone (11%). The median time on ICI was 3.1 (0.1-26.8) months, and the median PFS was 6.3 (95% CI, 0-18.6) months. Among the 21 patients with an evaluable response, the best ORR was 33%, including two complete responses and five partial responses. The ORR was 29% (n = 1 complete response, n = 5 partial response) in clear cell and 5% (n = 1 complete response) in non-clear cell RCC. Adverse events (AEs) of any cause were reported in 37% and included fatigue (11%), dermatitis (11%), diarrhea (7%), and shortness of breath (7%). Significant AEs (30%) included shortness of breath (7%), acute kidney injury (4%), dermatitis (4%), Clostridium difficile infection (4%), cerebrovascular accident (4%), and fatigue (7%). Three patients discontinued therapy due to grade 4 AEs. Barata et al. PD-1/PD-L1 Inhibitor Monotherapy in RCC Conclusions: In this multi-institutional case series, single-agent ICI demonstrated objective responses and was well tolerated in a heterogeneous treatment-naïve mRCC cohort. ICI monotherapy is not the standard of care for patients with mRCC, and further investigation is necessary to explore predictive biomarkers for optimal treatment selection in this setting.

Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?

“…Nivolumab has been tested as first-line monotherapy in the phase 2 studies of HCRN GU16-260 (NCT03117309) [98] and OMNIVORE (NCT03203473) [99], which produced modest results and had adverse effects similar to prior studies involving nivolumab. Retrospective experience with ICI monotherapy has reported similar outcomes [100]. While these are proof-of concept studies, they raise the question of whether ICI monotherapy is an effective treatment strategy.…”

Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

“…These findings were later supported by sub-analyses of the papillary subgroup from KEYNOTE-427, where the response rate was 28.8%. It should be noted that in all of the reported cohorts, both retrospective and prospective, durable responses have been documented [22].…”

A Systematic Review of Immune Checkpoint Inhibitors in Non-Clear-Cell Renal Cancer

“…Overall, the use of ICI monotherapy has a variable degree of efficacy in nccRCC across the included series. Some studies report outcomes in the range of what has been reported for the use of ICI monotherapy in the treatment of ccRCC [20,22,23] while others have poorer results [21,[24][25][26]. The expected efficacy of ICI monotherapy among ccRCC was considered to be near the one reported in CheckMate-025 (ORR 25%, mPFS 4.6 months; mOS 25 months) [5].…”

“…Overall, the higher ORR percentages were obtained in patients with an unclassified histology, with values as high as 44.4-66.7% [18,25]. Unclassified RCC includes different types of tumors with different behaviors, which can possibly explain the variability of outcomes between studies, with a lack of response and an ORR of 0% obtained in some series with a low number of these tumors [24,26].…”

“…Nevertheless, chromophobe patients had poorer results, with no documented responses to ICI monotherapy and an ORR of 0% across most studies [22][23][24][25][26] and with an ORR of 9.5% in one of the included studies using ICI monotherapy [20]. However, the ORR obtained among chromophobe patients improved with the use of combination regimens, with a value of 10% obtained with ICI-TKI [16] and a value of 20% obtained with an ICI-ICI scheme [18].…”